Prelich, Gregory Project Summary: This application addresses Broad Challenge Area 06 (Enabling Technologies) and Specific Challenge Topic 06-DA-103 (Identification of chemical modulators of epigenetic regulators). Post-translational modification of histones and other transcription factors can generate epigenetic changes in gene expression, and these modifications perform critical roles in development, differentiation, and human disease. A limited number of pharmacological agents currently exist to manipulate the activity of epigenetic modifying enzymes in vivo, with the HDAC inhibitors serving as a model for the field. The goal of this proposal is to identify small molecules that inhibit the SUMOylation pathway. This will be accomplished in two stages: (1) by performing a large-scale chemical genetic screen for compounds that inhibit the SUMO pathway in vivo, and (2) by performing secondary assays on the hits from the primary chemical genetic screen to identify those molecules that directly inhibit SUMOylation. Inhibitors identified through this project will serve as reagents for studying epigenetic modification of transcription by SUMO, with strong potential for broader application in elucidating the roles of SUMO in human health and disease. 1 Proteins are modified in many ways that affects their activity in the cell. A critically important yet poorly understood protein modification is called SUMOylation. Proteins that are involved in cancer, neural degeneration, microbial infection, and the immune response are all SUMOylated. A major stumbling block for further understanding the roles of SUMOylation is the lack of an effective drug that targets the pathway. The goal of this project is to take the first steps for developing a SUMO-specific drug.